Study of HGF Via Plasmid Vector to Improve Perfusion in Critical Limb Ischemia

A Phase II Double-Blind, Randomized, Placebo-Controlled Study to Assess the Safety and Efficacy of AMG0001 to Improve Perfusion in Critical Leg Ischemia

The primary purpose of this study was to assess the overall safety of different dose regimens of AMG0001 (HGF transferred via plasmid vector) as well as evaluate the improvement of blood perfusion in subjects with critical limb ischemia (CLI). This study also evaluated the improvement in wound healing without adverse effects on the quality of life, as well as the potential reduction of amputation, mortality and rest pain in the CLI population.

Study Overview

• Status: Completed
• Conditions: Ischemia; Peripheral Vascular Disease; Arterial Occlusive Disease
• Intervention / Treatment: Genetic: HGF plasmid

Detailed Description

The primary goal of this study was to assess the safety of AMG0001, detect potential angiogenesis response to AMG0001 treatment and to correlate these changes to clinical endpoints dependent upon improvement in tissue perfusion for relief of CLI complications. The objectives of this study were to:

• Assess the overall safety of different exposure regimens of AMG0001 in the CLI subject population.
• Evaluate the potential effect of angiogenesis associated with different doses and dose regimens of AMG0001 as measured by improvement in tissue perfusion.
• Evaluate the activity of different exposure regimens of AMG0001 to benefit clinical outcomes of reduction of amputation and mortality, wound healing, rest-pain reduction and improvement in subject's ability to function without adverse consequences on quality of life.

• Study Type: Interventional
• Enrollment (Actual): 104
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35211
      • Cardiology, P.C.
  • Arkansas
    • Little Rock, Arkansas, United States, 72205
      • Central Arkansas Veteran's Healthcare System
  • California
    • Los Angeles, California, United States, 90048
      • Cedars-Sinai Medical Center
    • Stanford, California, United States, 94305
      • Falk Cardiovascular Research Center
  • District of Columbia
    • Washington, District of Columbia, United States, 20422
      • VA Medical Center Surgical Service (112)
  • Florida
    • Pensacola, Florida, United States, 32501
      • Basptist Hospital
    • Tampa, Florida, United States, 33606
      • University of South Florida College of Medicine
  • Georgia
    • Atlanta, Georgia, United States, 30342
      • American Cardiovascular Research Institute
  • Illinois
    • Chicago, Illinois, United States, 60637
      • University of Chicago Hospitals
  • Indiana
    • Indianapolis, Indiana, United States, 46290
      • The Care Group, Llc
  • Louisiana
    • Metairie, Louisiana, United States, 70002
      • The Ochsner Heart and Vascular Institute
  • Minnesota
    • Minneapolis, Minnesota, United States, 55407
      • Minneapolis Heart Institute Foundation
  • New Hampshire
    • Lebanon, New Hampshire, United States, 03756
      • Dartmouth - Hitchcock Medical Center
  • New York
    • New York, New York, United States, 10003
      • Diabetes Foot and Ankle Center
    • New York, New York, United States, 10021
      • NYPH-NY Weill Cornell Medical Center
    • Rochester, New York, United States, 14642
      • University of Rochester
  • North Carolina
    • Greenville, North Carolina, United States, 27834
      • Pitt County Memorial Hospital
  • Ohio
    • Cincinnati, Ohio, United States, 45219
      • The Lindner Clinical Trial Center
    • Cleveland, Ohio, United States, 44195
      • The Cleveland Clinic Foundation
    • Toledo, Ohio, United States, 43614
      • Medical College of Ohio
    • Toledo, Ohio, United States, 43606
      • Jobst Vascular Center
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • University of Oklahoma Health Sciences Center
  • Texas
    • Houston, Texas, United States, 77030
      • Baylor College of Medicine
    • San Antonio, Texas, United States, 78215
      • Peripheral Vascular Associates

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Subjects will have one or more clinical indications diagnostic of CLI such as: distal extremity pain at rest that requires the subject to use analgesics for >2 weeks; or peripheral ischemic ulcer(s); or areas of gangrene.
• The subject will have a TcPO2 of </= 40 mmHg.
• Subjects will have one or both of the following hemodynamic indicators of severe peripheral arterial occlusive disease: (a) Ankle systolic pressure of </= 70 mmHg; (b)Toe systolic pressure </= 50 mmHg.
• The subject is a poor candidate for standard revascularization treatment options for peripheral arterial disease, based on inadequate bypass conduit, unfavorable anatomy, or poor operative risk.
• Subject has signed an informed consent form either directly or through a legally authorized representative
• If female, the subject must be (a) at least one year post-menopausal, or (b) surgically sterile, or (c) if the subject is of child-bearing potential, she must have been practicing contraception for at least 12 weeks prior to entering the study.
• If subject is of reproductive potential, he or she must be using an accepted and effective (barrier) form of birth control during the study.
• Subjects will be on a statin and an anti-platelet agent as part of their standard of care and must be stable on these regimens for at least 4 weeks prior to treatment.

Exclusion Criteria:

• Subjects, who in the opinion of the investigator, have a vascular disease prognosis that indicates they would require a major amputation (at or above the ankle) within 4 weeks of start of treatment.
• Subjects with a diagnosis of Buerger's disease (Thromboangitis Obliterans).
• Subjects with hemodynamically significant aorto-iliac occlusive disease.
• Subjects who have had a revascularization procedure within 12 weeks prior to treatment initiation that remains patent. Revascularization procedures that are evidenced to have failed for >2 weeks prior to treatment initiation are acceptable.
• Subjects who require a change in their hypertension medication as part of their standard of care within 4 weeks prior to treatment.
• Evidence or history of malignant neoplasm (clinical, laboratory or imaging), except for basal cell carcinoma of the skin.
• Subjects who have proliferative diabetic retinopathy or severe, non-proliferative retinopathy
• Subjects with end stage renal disease (ESRD) defined as significant renal dysfunction evidenced by a creatinine of > 2.5, or receiving chronic hemodialysis therapy.
• A subject who has hepatic cirrhosis, viral hepatitis, or is HIV positive.
• Subjects with a clinically significant liver enzyme abnormality (i.e., AST or ALT more than two times the upper limit of normal and/or bilirubin more than 50% the upper limit of normal).
• Subjects requiring the use of hyperbaric oxygen treatment for wound healing during the screening and 6 month follow-up period.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: 1; 0.4 mg AMG0001 on days 0, 14, and 28	Genetic: HGF plasmid; Intramuscular injections into index leg on Days 0, 14, and 28
Active Comparator: 2; 4.0 mg AMG0001 on days 0, 14, and 28	Genetic: HGF plasmid; Intramuscular injections into index leg on Days 0, 14, and 28
Active Comparator: 3; 4.0 mg AMG0001 on days 0 and 28; placebo on day 14	Genetic: HGF plasmid; Intramuscular injections into index leg on Days 0, 14, and 28
Placebo Comparator: 4; Placebo (saline) on days 0, 14, and 28	Genetic: HGF plasmid; Intramuscular injections into index leg on Days 0, 14, and 28

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Tissue perfusion as measured by TcPO2	6 months

Secondary Outcome Measures

Outcome Measure	Time Frame
Ulcer healing	6 months

Collaborators and Investigators

• Sponsor: AnGes USA, Inc.

Publications and helpful links

General Publications

• Powell RJ, Simons M, Mendelsohn FO, Daniel G, Henry TD, Koga M, Morishita R, Annex BH. Results of a double-blind, placebo-controlled study to assess the safety of intramuscular injection of hepatocyte growth factor plasmid to improve limb perfusion in patients with critical limb ischemia. Circulation. 2008 Jul 1;118(1):58-65. doi: 10.1161/CIRCULATIONAHA.107.727347. Epub 2008 Jun 16.

Study record dates

Study Major Dates

• Study Start: April 1, 2003
• Primary Completion (Actual): May 1, 2006
• Study Completion (Actual): January 1, 2007

Study Registration Dates

• First Submitted: May 15, 2003
• First Submitted That Met QC Criteria: May 15, 2003
• First Posted (Estimate): May 16, 2003

Study Record Updates

• Last Update Posted (Estimate): January 11, 2008
• Last Update Submitted That Met QC Criteria: January 9, 2008
• Last Verified: January 1, 2008

More Information

Terms related to this study

• Keywords: Critical Limb Ischemia
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Arteriosclerosis; Atherosclerosis; Vascular Diseases; Ischemia; Peripheral Arterial Disease; Peripheral Vascular Diseases; Arterial Occlusive Diseases
• Other Study ID Numbers: AG-CLI-0202